Development of Novel ¹¹C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [C-11]1([C-11]OX2-2201) and [C-11]2([C-11]OX2-2202) as novel PET ligands. Both compounds1(K-i= 3.6 nM) and2(K-i= 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1> 600 folds).In vitroautoradiography in the rat brain suggested good to excellentin vitrobinding specificity for [C-11]1and [C-11]2. PET imaging in rat brains indicated that the low brain uptake of [C-11]2may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.